Conventional needles have long been used to deliver drugs and other substances to humans and animals through the skin. The skin is made up of several layers, with a series of upper composite layers residing in the epidermis. The outermost layer of the epidermis is the stratum corneum, which has well known barrier properties to prevent molecules and various substances from entering the body and analytes from exiting the body. The stratum corneum is a complex structure of compacted keratinized cell remnants having a thickness of about 10–30 μm. The stratum corneum forms a waterproof membrane to protect the body from invasion by various substances and the outward migration of various compounds. This natural impermeability of the stratum corneum prevents the administration of most pharmaceutical agents and other substances through the skin. Following the stratum corneum, a further series of additional layers support the stratum corneum and comprise the rest of the epidermis. All of these layers together with the stratum corneum extend to a depth of between about 50 and 100 μm. The dermis follows the epidermis beginning at a depth of about 50–120 μm below the skin surface in humans and is approximately 1–2 mm thick. The dermis contains small capillaries and the beginnings of the nerve bed. Below the epidermis and dermis, the outer layers of the skin, lay the hyperdermis, fat layers and muscles with connective tissues.
Currently, the vast majority of medicaments that enter the body from without are injected through the skin into these regions underlying the epidermis and dermis, through both the Intramuscular (IM) and subcutaneous (SC) injection routes, directly into these tissues. In both of these typical injections routes, a needle penetrates through the various layers of the skin to the areas below the skin and the medicament is introduced through injection. The needles used for such injections are typically large gauge needles. Various advances in needle design over the years have allowed for the use of needles with sharper tips and, in some cases, smaller diameters in an attempt to mitigate the pain and damage to surrounding tissues caused by these injection routes. However, a great deal of discomfort and pain associated with the IM and SC delivery routes remains.
Numerous methods and devices have been proposed to introduce medicaments through the outer layers of the skin to avoid the intrusive, painful IM and SC delivery routes. The methods and apparatus for using this delivery route generally either increase the permeability of the skin by abrasion or increase the force or energy used to direct the drug through the skin. An example of such a device is a microabrader, which makes microscopic cuts in the skin to enhance permeability and, thereby, allows the medicaments to penetrate into the body without the need for injection. These devices typically utilize a plurality of microscopic blades or needles to abrade the stratum corneum. However, the technology to produce the microscopic blades or protrusions is still in its early development. Although there are several ongoing attempts to develop commercially effective ways of forming the microscopic blades, significant progress still needs to be made, especially in the area of microcannulas, in particular steel microcannulas.
Another route for introducing some types of medicaments into the body through the upper layers of the skin in a relatively painless and unobtrusive manner is by injection between the epidermal and dermal layers, the so-called intradermal (ID) injection. Recent advances in drug delivery systems and smaller gauge, microcannula have made the ID injection route a viable and promising alternative to the IM and SC injection routes for the delivery of some medicaments. ID administration and removal of drugs and other substances has several advantages over the traditional injection routes. The intradermal space is close to the capillary bed and allows for absorption and systemic distribution of the substances. In addition, there are more suitable and accessible ID injection sites available for a patient as compared to currently recommended SC administration sites.
Although attempts have been made to use the large gauge needles used in IM and SC injections to target delivery or extraction in the ID injection site, these attempts have generally been ineffective and inefficient. Using large gauge needles to target the ID delivery site requires special injection techniques, which are difficult to perform even if a trained professional is administering the injection. These techniques typically require the professional to maneuver the large gauge needle to the intradermal target site manually. This is prohibitively difficult as the ID injections occur in such a small target site just beneath the epidermis in the interface with the dermis. These larger gauge needles are often themselves larger in diameter than the target site. As a result, pain of insertion and the possibility of missing the target makes these systems and techniques impracticable.
However, the aforementioned advances in smaller gauge cannula technology have made the ID injection route a more plausible alternative. Of particular interest for the ID injection route are microneedles or microcannulas, which are typically less than 0.3 mm in mean diameter and less than 2 mm in length. They may be used in a variety of devices, including pen injection devices, arrays of multiple microneedles, micro pumps, and other medical devices. Microcannula benefit from the aforementioned design advances, having very sharp and short tips. The sharpness reduces the penetration force and discomfort felt by the patient resulting from the initial stick. The smaller diameter and sharper cannulas also reduce tissue damage and therefore decrease the amount of inflammatory mediators released during the ID injection. The short tip of the microcannula also facilitates drug delivery near the surface of the skin, without any fluid leakage. The size of the microcannula also allows for accurate targeting of the intradermal space, thus avoiding the need for the special insertion procedures that are currently used to reach this injection site with large gauge needles. The heretofore known microcannula are usually fabricated from silicon, plastic or, sometimes, metal and may be hollow for delivery or sampling of substances through a lumen.
A limiting factor in improving these drug delivery technologies has been the cost of forming and finishing both the improved, sharper large gauge cannula and the smaller gauge microcannula. In the typical production of large gauge cannula, significant costs are associated with forming and finishing the needles. Examples of this typical process are seen in U.S. Pat. No. 4,413,993 to Guttman, U.S. Pat. No. 4,455,858 to Hettich and U.S. Pat. No. 4,785,868 to Koeing Jr. The typical process begins with a flat stainless steel strip or blank. The steel strip is rolled and welded into a large gauge hollow tube. The large gauge tube is progressively drawn or otherwise cold worked down to achieve smaller gauge stock tubing, as shown in the aforementioned patents. This cold working simultaneously work hardens the tube. For instance, in both Hettich and Koeing the stock is stamped in a die, which work hardens the resulting cannula. The stock is then cut to length, forming cannula, which are then finished by conventional finishing means to provide a desired tip shape, typically a sharpened beveled tip. Even though improved finishing techniques, like those related by U.S. Pat. No. 5,515,871 to Bittner et. al. utilizing laser cutting, may be slightly more efficient than conventional techniques, the costs associated with finishing are still significant. Typically any additional finishing after the cannula is formed adds costs to the cannula as a result of, for example, increased production time, added machinery costs, and added variances in quality.
Although cutting methods for wire utilizing a heated zone and were known as early as 1965, as related in IBM Technical Disclosure Bulletin, September 1965, page 633, and more specifically, in German patent DE7221802 to Bündgens, directed to such a wire cutting apparatus. The IBM TDB only suggests giving a wire a “bullet nose” for threading proposes, and the Bündgens patent only suggests separation of wire or tubing into unitized portions and further processing of the unitized portions into needles, pins or the like. The further processes in secondary operations, as discussed previously, are at additional expense and processing time.
These costs are magnified as the cannula gauge is reduced. The processes described above are typically used for forming large gauge wires or conventional cannula and can be used commercially to produce cannula as small as 34 gauge. However, it is cost prohibitive to achieve finished needles at such a small gauge. Additionally, significant quality control problems arise from the application of conventional finishing techniques to these small gauge needles, including burring that clogs the hollow cannula and causes unwanted aberrations in the finished points.
Unlike the large gauge cannula, no cost-effective manner of mass production has been found to date for microcannula, especially durable steel or other metallic microcannula, smaller than 34 gauge. Although several attempts have been made at fabricating smaller microcannula, they have not been commercially successful. Moreover, the lack of a cost effective fabrication process for microcannula, especially durable steel microcannula, hampers development of devices capable of targeting the preferred ID injection site.
The heretofore known methods of mass-producing microcannula smaller than 34 gauge have been based predominantly on silicon microfabrication processes, such as etching, vapor deposition or masking. The current silicon, glass and plastic microcannula produced by these methods lack the durability necessary for effective use in ID injection devices. Devices such as those seen, for example, in the papers entitled Transdermal Protein Delivery Using Microfabricated Microneedles (Georgia Institute of Technology, S. Kaushik et al., October/November 1999), Microfabricated Microneedles: A novel Approach to Transdermal Drug Delivery, Sebastien Henry et al., Journal of Pharmaceutical Sciences, Volume 87, pgs. 922–925; and Solid and Hollow Microneedles for Transdermal Protein Delivery, Proceed. Int'l Symp. Control. Rel. Bioact. Mat., 26 (Revised July 1999), pgs. 192–193), or as seen in U.S. Pat. No. 5,801,057, U.S. Pat. No. 5,879,326 and International Patent Application WO 96/17648 utilize silicon etching and other standard microprocessor manufacturing technologies to produce hollow cannula. Utilization of such manufacturing techniques is costly and provides cannulas with only limited durability, as silicon microcannula are brittle and subject to fracture during use.
Various other manufacturing processes have been applied to plastic and glass microcannulas, see for example U.S. Pat. No. 5,688,247 to Waitz et al and U.S. Pat. No. 4,885,945 to Chiodo, which show plastic and glass devices with tapered, beveled and closed plastic and glass tips. These devices are similarly not suitable for use in injections as they are fragile or not rigid enough to accurately target the ID injection site.
There remain no enabling technologies, to date, to make commercially viable microcannulas available in gauges smaller than 34 gauge, especially from steel or other durable metals. Further, there are no cost effective, commercially available steel microneedles or microneedles with conical, tapered or bevel shaped tips. Additionally, it would be desirable for a process to result in a near-net-shape unitized portion of cannula, such that it may be additionally processed with minimal effort into a finished small gauge cannula.